Acid suppression and the gastric flora

8

Acid suppression and the gastric flora R. V. HEATLEY G. M. SOBALA

Until recent years the stomach and upper small intestine were believed to be relatively sterile (Hill, 1986; Drasar, 1989). The normal acid stomach (pH<4) has most commonly been found to have a sparse flora, consisting mainly of organisms from the mouth that have been swallowed with food or saliva and in the process of dying as a result of gastric acid. The major controlling factor for bacterial survival in the stomach thus appears to be pH. When pH is greater than 4 but less than 5 salivary organisms survive, particularly acid-tolerant lactobacilli and streptococci. Above pH 5 a resident gastric flora exists, including faecal streptococci and bacteroides (Hill, 1986; Drasar, 1989). This change is exemplified by studying the gastric bacterial flora of patients with pernicious anaemia and those who have had previous gastric surgery, which frequently contains faecal-type organisms such as Streptococcus faecalis and Bacteroides fragilis, which are also bile resistant. The jejunum and duodenum are also usually relatively free of bacteria in health. The sparse flora is due probably to the few live organisms entering from an acid stomach and the antibacterial effect of bile and pancreatic juice (Hill, 1986). In individuals with achlorhydria, small numbers of bacteria can be detected in jejunal juice but large numbers of organisms are only found in the presence of duodenal or jejunal diverticulae, blind loops or following previous gastric surgery (Drasar et al, 1.969). Our understanding of gastric and duodenal flora has been transformed by the discovery of Helicobacterpylori. This fascinating organism is now recognized to colonize the stomach in the majority of patients with active chronic gastritis and also those with peptic ulceration. It colonizes the duodenum as well in the presence of gastric metaplasia in most patients with chronic active duodenitis. H. pylori is found in the stomach in almost one-half to two-thirds of most populations, depending on the age and socioeconomic circumstances of those studied. The organism is of particular interest in relation to acid secretion since it is itself rapidly killed in an acid environment when the pH is less than 4 (Tompkins, 1989). The presence of this organism may also have effects on acid secretion by means of its association with elevated levels of circulating gastrin, although this is not completely resolved at present. Bailli2re’s Clinical GastroenterologyVol. 7, No. 1, March 1993 ISBN @7020-1733-7

167 Copyright 0 1993, by Baillibre Tindall All rights of reproduction in any form reserved

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FACTORS

Low pH is principally responsible for the bactericidal properties of gastric juice. The lack of bacteria in the stomach of fasting subjects and the normal diminution in the bacterial content of the stomach after a meal are both related to the acidity of gastric juice. The importance of gastric acidity is reflected in the concern about the effects of antisecretory agents on gastric flora (Stockbruegger et al, 1982). It is of interest that geographical variations in normal gastric flora have been reported, and nutritional factors may be responsible for this (Gilman et al, 1988). The variation in types of bacteria isolated from the gastric contents of individual patient groups cannot, however, be explained entirely by differences in acid secretion. Adhesion to the gastric mucosa is a major determinant of the ability to colonize the stomach in animals, and bacteria of various types have been reported to be adherent to human gastric mucosa. The mucous layer within the stomach is probably of major importance in protecting adherent bacteria, of whatever type, from gastric acid. By such means it is possible that a biofilm ecosystem exists, as has been described at other mucosal surfaces, including the intestine and vagina (Costerton et al, 1987). In the case of a gastric mucous biofilm ecology, pH control would be expected to be particularly important. In this regard the urease activity of H. pylori, for instance, may be an example of how a local mechanism could exert influence on the environment of an organism within the stomach. Another factor which may also be important in colonization is selection of those organisms that colonize when acid secretion is impaired. Receptors on the gastric mucosa could determine which bacteria are able to colonize, only those with suitable cell wall ligands being able to gain a permanent presence. NORMAL

GASTRIC

FLORA

In fasting gastric juice there appears general agreement that the numbers of organisms are relatively low, approximately lo*-10’ organisms/ml, or, alternatively, the juice may be entirely sterile. A mixed bacterial and yeast population can occur transiently in gastric juice after eating or drinking. These organisms usually represent those normally found in the mouth and pharynx, and include aerobic streptococci, staphylococci, lactobacilli and candida, but others can also be present (Drasar et al, 1969).

GASTRIC

FLORA

IN PATHOLOGICAL

STATES

Intragastric contents often contain increased numbers of bacteria in patients with pernicious anaemia, usually with counts of about lo5 organisms/ml. However, these may rise to as much as 106-10’ organisms/ml. The spectrum of organisms also frequently changes, and often includes coliforms,

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bacteroides and other ‘faecal-type’ organisms which are not usually present within the stomach (Drasar et al, 1969; Stockbruegger et al, 1984; Stockbruegger , 1985). Similar changes occur as in pernicious anaemia in some patients after gastric surgery, especially following partial gastrectomy or vagotomy and antrectomy, often in the range of lo4 organisms/ml. Vagotomy alone, however, does not appear to be associated with these changes (Drasar and Shiner, 1969; Drasar et al, 1969; Thomas et al, 1987). During treatment with histamine Hz-receptor antagonists total gastric juice bacterial numbers tend to rise (Ruddell et al, 1980). Numerous studies (see below) have reported increased numbers of nitrate-reducing organisms and luminal nitrite concentrations during Hz-receptor antagonist drug treatment (Stockbruegger, 1985; Thomas et al, 1987). Data are far more limited with more potent inhibition of gastric acid secretion, with agents such as the proton pump inhibitor, omeprazole. However, in one study, bacterial counts rose to 6 x lo7 organisms/ml during treatment, with concurrent increases in the numbers of nitrate-reducing bacteria and nitrite concentrations comparable with those observed with Hz-receptor antagonist treatment (Sharma et al, 1984). These changes are not, however, consistent in all individuals and those who did show changes only did so during continued treatment. CONSEQUENCES

OF ACID SUPPRESSION

Reduction of gastric acid secretion has frequently been suggested to predispose to infection with a variety of organisms including salmonella, shigella, Vibrio cholerae, brucella and parasites including giardia and strongyloides (Hunt, 1989). However, these observations have been made in various circumstances and there may be no general rules related to risk (Howden and Hunt, 1987). For instance, previous gastric surgery appears a significant risk factor for salmonella infections related directly to the reduction in gastric acid secretion (Waddell and Kunz, 1956). Gastric acid secretion tends to decrease with age and this may be responsible for the increased likelihood of elderly patients developing severe salmonella infection (Grossman et al, 1963; Gorbach, 1983). Cholera is also most likely to occur and to be more severe in the presence of reduced acid secretion since it is known that cholera bacilli are markedly acid sensitive (Sack and Carpenter, 1969; Gitelson, 1971; Nalin et al, 1978). Another area in which bacterial overgrowth may give rise to clinical problems, but in a different context, is in intensive care medicine. Because bleeding from stress-induced erosions is a significant hazard in patients nursed in intensive care units, acid-suppressive treatment has been used widely to reduce both the volume and acidity of gastric secretions. Recently it has become apparent that the rise in gastric pH caused by such treatment is accompanied by overgrowth of gastric juice with potential pathogens, including Klebsiellu and Pseudomonas spp. (Mauritz et al, 1985). This may give rise to an increased incidence of nosocomial pneumonias (Daschner et

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al, 1988; Lehot et al, 1990), but this has not been a uniform finding in all studies (Simms et al, 1991). By contrast, sucralfate may exert an antibacterial effect on gastric juice at the same time as protecting against stress erosions, and some authors have claimed that this drug should be used in preference to the Hz-receptor antagonists as it decreases the incidence of nosocomial pneumonia in intensive care unit patients (Tryba and ManteyStiers, 1987; Daschner et al, 1988). ACID

SUPPRESSIQN

AND GASTRIC

CANCER

There is particular concern that suppression of gastric acid secretion may increase the risk of gastric cancer. The currently accepted hypothesis of the aetiology of gastric cancer is that proposed by Correa and co-workers (Correa et al, 1975; Correa, 1983, 1988), in which it is suggested that gastric cancer is the last of a series of ‘mutations’. The first step is likely to be the conversion of normal to gastritic mucosa by infection with H. pylori. In some patients with chronic gastritis glandular atrophy develops, with a consequent reduction in gastric acid output. This step may be an inherent result of chronic H. pyZori infection, due to dietary factors such as salt consumption, or may in part be genetically determined. The rise in gastric juice pH allows bacterial overgrowth to occur. Some bacteria (but not H. pylori) are capable of reducing dietary nitrate to nitrite, which in turn can form a number of highly reactive chemical species, such as NzOs and the nitrosyl ion NO+. These can react in aqueous solution with amines, amides and other molecules to form the corresponding N-nitrosocompounds (NOC), many of which are mutagenic. According to the hypothesis, these then act on the gastric epithelium to cause a sequence of mutations resulting in, first, intestinal metaplasia, then dysplasia and, finally, carcinoma. This is a powerful hypothesis which is supported by much experimental evidence. Firstly, there is a clear association between an increased risk of gastric cancer and three states characterized by hypochlorhydria: pernicious anaemia (Mosbech and Videbaek, 1950; Caygill et al, 1986, 1987), hypogammaglobulinaemia and partial gastrectomy (Tersmette et al, 1990). Secondly, it is a consistent finding in a large number of studies that gastric juice nitrite concentration rises in parallel with pH and the extent of bacterial overgrowth (see, for example, Ruddell et al, 1976). Whereas most of the nitrite found in acid gastric juice is derived from saliva, more than 90% of that in juice of pH greater than 4 is gastric in origin. Patients with chronic atrophic gastritis and hypochlorhydria, but not controls, show substantial increases in gastric nitrite after ingestion of a fixed amount of consumed nitrate (Eisenbrand et al, 1984). Thirdly, most epidemiological studies have reported a positive association between gastric juice nitrite concentrations and the incidence of gastric cancer or its precursor lesions (Correa et al, 1970; Tannebaum et al, 1979; Chen et al, 1990). One study has reported the contrary: in New Orleans Blacks, more severe gastric lesions were associated with lower nitrite

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concentrations. This was attributed to the particular diet of the population in question: the chief source of nitrate was vegetables that were also rich in antioxidants which could, therefore, potentially exert a protective action against gastric carcinogenesis (Fontham et al, 1986). Fourthly, it has been shown experimentally that nitrosation can occur in human gastric juice in vivo: administered nitrite or nitrate and proline lead to the production of nitrosoproline (which is not a carcinogen) (Ohshima and Bartsch, 1981). Fifthly, it is a consistent epidemiological finding that a high dietary consumption of antioxidants, including ascorbic acid and cr-tocopherol, is protective against gastric cancer. Antioxidants, particularly ascorbic acid, inhibit N-nitrosation reactions by scavenging nitrite. Finally, treatment of food products with nitrite does yield potent mutagens and the products do cause tumours in animal models (Weisburger et al, 1980; Wakabayashi et al, 1989). The main weakness of the Correa hypothesis is its dependence on NOC as the mutagenic agents. Chemical nitrosation is favoured by acid rather than neutral pH; the optimum pH for the nitrosation of amines is around 3-4, whilst the nitrosation of amides increases with decreasing pH (Mirvish, 1975, 1983). At such pH ranges, bacterial overgrowth is rare and nitrite concentrations are low. As it is not known which (if any) of the NOC are biologically relevant, and it has not been practical to measure them individually, a variety of methods have been developed to measure NOC as a group. Unfortunately, these methods have major shortcomings in terms of poor sensitivity (for example, the method of Walters et al (1978) which fails to detect the more unstable NOC) or specificity (for example, the method of Bavin et al (1982) which suffers from interference by non-NOC nitric oxide-releasing compounds). To some extent these difficulties have been resolved (Pignatelli et al, 1987), but it remains true that in most cases the nature of the compounds that are actually being detected with these techniques is unknown. According to the method of Walters et al (1978), NOC concentrations are higher at neutral pH, in the presence of bacterial overgrowth, and are correlated with nitrate concentrations (Reed et al, 1981a). This is in accord with the Correa hypothesis. However, studies using the method of Bavin et al (1982) have yielded directly contrary results: NOC concentrations were found to be higher in juice samples of acid pH (Keighley et al, 1984; Hall et al, 1986). Few studies to date have used the method of Pignatelli, but those published have not found high NOC levels at neutral pHs (Pignatelli et al, 1987; Sobala et al, 1991). ACID SUPPRESSION

AND THE CORREA

HYPOTHESIS

Although most studies have demonstrated increases in gastric microflora treatment with drugs that suppress gastric acid secretion (Ruddell et 1978; Ruddell et al, 1980; Muscroft et al, 1981a; Snepar et al, 1982; Long al, 1983), a few have failed to do so (Bourne et al, 1984; Stockbruegger et

on al, et al,

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1988). The likelihood of finding overgrowth will increase with the gastric juice pH, and studies in which gastric juice has been obtained after a prolonged fast are more likely to find such a raised pH. However, this is probably not physiological. Certainly, in subjects taking maintenance cimetidine with food, hypochlorhydria and raised nitrite concentrations were not found (Muscroft et al, 1981b). The results of studies that have specifically looked at the effect of acidsuppressive therapy on NOC concentrations are confusing. Apart from depending on which method was used to estimate NOCs, results have varied according to whether samples were stored prior to analysis. The timing of juice collection has also differed. Several studies have relied on juice collected after a prolonged fast. As mentioned previously, this is not physiological and has probably given unrepresentative results. Other studies have relied on multiple sampling over a 24-h period. Another confounding variable is the fact that some studies have used normal volunteers, whereas others have used patients with duodenal or gastric ulcer: the natural acid-secretory capacity of the stomach is likely to differ between these groups. Most studies using the Walters method have demonstrated higher NOC concentrations in subjects treated with acid-suppressants such as cimetidine (Reed, 1981b; Stockbruegger et al, 1982) and omeprazole for 2 weeks (Sharma et al, 1984). NOC concentrations correlated with nitrite levels and bacterial counts. However, in a study using the Walters method and multiple sampling over a 24-h period, maintenance treatment with ranitidine for 1 year increased nitrite concentrations and bacterial counts, but not NOC concentrations. The authors noted that although bacterial counts were increased at some point in each day, an acid tide prevented persistent bacterial colonization. All parameters returned to normal a few weeks after cessation of therapy (Meyrick Thomas et al, 1987). In a study using the Bavin method and 24-h sampling, no overall increases in nitrite or NOC were seen as a result of cimetidine treatment (MiltonThompson et al, 1982). Nitrite concentrations did, however, correlate with pH. In a cimetidine-treated pig model, there was little nitrosation of trimethylurea despite bacterial overgrowth and high nitrite concentrations (Maragos et al, 1991). The Bartsch test has also yielded data contrary to the Correa hypothesis, probably because nitrosation of proline is acid catalysed. Studies have tended to show lower levels of nitrosoproline formation in patients with drug-induced or pathological hypochlorhydria (Elder et al, 1984; Hall et al, 1987). However, a recent modification to this test, in which subjects are fed only proline without excess nitrate, may prove to be of more relevance to carcinogenesis; nitrosation of proline will then depend more on intrinsic nitrite concentrations (Houghton et al, 1989). The Hz-recep.tor antagonists themselves can be nitrosated under certain conditions, and the resulting nitroso-derivatives may be mutagenic (de Flora et al, 1983, 1986). However, these reactions require excess nitrite and acid juice, and there has been little evidence to suggest that this occurs in clinical use. The phenomenon is probably of little significance.

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Some studies have attempted to circumvent the problem of identifying specific mutagenic compounds by instead measuring the mutagenicity of gastric juice. However, these studies also give conflicting results, and it appears that there are several methodological pitfalls with mutagenicity testing. In one study, there was no significant increase in mutagenicity of gastric juice after treatment with ranitidine or cimetidine (O’Connor et al, 1987). By contrast, famotidine, a more potent Hz antagonist, was found to produce a nocturnal plateau of increased mutagenicity; this was attributed to the rise in pH rather than the formation of any famotidine-derived mutagens (de Flora et al, 1987). The results of the NOC studies do not overturn the Correa hypothesis, and probably reflect failures in methodology rather than the hypothesis. There are alternatives to chemically-catalysed nitrosation. It has been discovered that bacteria can directly catalyse N-nitrosation reactions at neutral pH (Calmels et al, 1985). A nitrosating enzyme has been isolated (Calmels et al, 1990) and a responsible gene may have been identified (Ralt et al, 1988). There is great variation between clinical isolates in nitrosating capacity (O’Donnell et al, 1988), and therefore both nitrite and bacterially catalysed NOC production in the stomach is probably very dependent on precisely which species and strains are present (Leach et al, 1987; Forsythe et al, 1988). It has been estimated that at neutral pH, under some conditions, bacterial nitrosation could be 100 times faster than chemical nitrosation. Furthermore, there is evidence for in vivo production of NOC in rats treated with omeprazole who have nitrosating species in their stomachs (Calmels et al, 1991). It is also possible that endogenous production of nitric oxide, via nitric oxide synthetase in the gastric mucosa, may be important in carcinogenesis. Macrophages can be stimulated to produce nitric oxide and nitrosocompounds by bacterial lipopolysaccharide (Leaf et al, 1991). Thus, there is good evidence for associations between hypochlorhydria, bacterial overgrowth, high nitrite concentrations and gastric cancer. The ‘missing links’ in the Correa hypothesis are the NOCs. The tools used to measure these to date have been too crude; future work will concentrate more on identifying and quantifying specific mutagens. Therefore, the absence of a definite association between acid-suppressive treatment and elevated concentrations of NOCs is not particularly reassuring, as it is clear that if acid-suppressive treatment is potent enough to produce hypochlorhydria, bacterial counts and nitrite concentrations do rise. The possibility of an adverse risk with long-term treatment cannot as yet be excluded on theoretical grounds; the risk is likely to be proportional to the degree of acid inhibition. GASTRIC

JUICE

ASCORBIC

ACID

There is also a possibility that acid-suppressive therapy may contribute to gastric cancer risk by effects on gastric juice ascorbic acid concentrations. Ascorbic acid is the reduced form of vitamin C, whereas the oxidized form is dehydroascorbic acid. Ascorbic acid, but not its dehydro- form, is a

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powerful antioxidant that may be able to protect against gastric cancer by scavenging nitrite. It also inhibits nitrosation catalysed by bacteria (Mackerness et al, 1989). It has recently been discovered that vitamin C is secreted in high concentrations into the gastric juice by the healthy stomach. This secretion is substantially impaired in the presence of H. pylori-associated chronic gastritis. Chronic H. pybri infection has itself been associated with the subsequent development of gastric cancer (Forman et al, 1991; Nomura et al, 1991; Parsonnet et al, 1991). Whereas at acid pH most vitamin C is in the form of ascorbic acid, in gastric juice samples from patients with chronic gastritis with an elevated pH all that remains is ‘spent’ dehydroascorbic acid {O’Connor et al, 1989; Rathbone et al, 1989; Sobala et al, 1989, 1991). Treatment of duodenal ulcer patients with either omeprazole or cimetidine, at a dose sufficient to raise gastric pH above 5, causes gastric juice ascorbic acid concentrations to fall to near zero. Furthermore, such gastric juice samples actively destroy added ascorbate in vitro (Schorah et al, 1991). DOES ACID SUPPRESSION

AFFECT H. PYLORZ?

Increased acid load is recognized to be an important factor in the development of gastric metaplasia within the duodenum, which in itself is recognized to be associated with duodenal colonization with H. pylori (Wyatt et al, 1987). The effects of antacids on H. pylori colonization have not been extensively investigated. However, there is little evidence of in vitro or in vivo efficacy against this organism. Similarly neither do HZ-receptor antagonists, nor pirenzepine or the mucosal protective agents, which include sucralfate and the prostaglandin analogues, influence H. pylori colonization of gastric mucosa (Rauws and Tytgat, 1989). Some data have suggested that the powerful acid suppressor, omeprazole, a proton pump inhibitor which inhibits H. pylori in vitro, may affect H. pylori colonization, especially in combination with antibiotic therapy. Although most studies have shown no convincing evidence that this agent alone brings about H. pylori eradication, a few small studies suggest that the combination of amoxycillin with omeprazole may have some limited efficacy greater than with either agent used alone (Unge et al, 1989). Whether this is because of acid inhibition alone or whether pH alterations affect the absorption or bioavailability of amoxycillin within the gastric mucosa in unknown. Bismuth-containing preparations are clearly effective both in vitro and in vivo and produce eradication of H. pylori from the stomach (Rauws and Tytgat, 1989). Although results with monotherapy are disappointing, they are excellent when bismuth is used in combination with two antibacterials such as tetracycline or amoxycillin and metronidazole or tinidazole. Colloidal bismuth subcitrate is known to retard hydrogen ion diffusion within the stomach and increase total prostaglandin and bicarbonate secretion, which may all influence intragastric pH. It appears unlikely, however, that these physiological responses are relevant to the observed action of bismuth against H. pylori colonization (Rauws and Tytgat, 1989). The incidence of H. pylori infection appears to fall with time after gastric

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surgery, with lowest positivity rates in patients who have had a partial gastrectomy or vagotomy and gastroenterostomy (O’Connor et al, 1986). CONSEQUENCES OF BACTERIAL ACID SECRETION

INFECTION

ON GASTRIC

Chronic H. pylori infection of the gastric antrum is now widely agreed to be associated with increased circulating levels of gastrin. Furthermore, eradication of 4-1.pylori leads to a marked reduction in gastrin concentrations. The effect of H. pylori infection on gastric acid secretion is, however, less clearly defined, as is the reason for H. pylori infection being associated with hypergastrinaemia. Levi et al (1989) suggested that pentagastrin-stimulated gastric acid secretion was higher in H. pylori-positive duodenal ulcer subjects than in similar patients without infection (Calam et al, 1991). However, this observation has not been confirmed by others. There is, in fact, little evidence to confirm that the changes in plasma gastrin concentrations with chronic H. pylori infection have any significant effects on gastric acid secretion (McCall et al, 1989). In acute H. pylori infection there is a suggestion of temporary effects on gastric acid secretion. However, the documentation of alterations in gastric acid secretion in two volunteer ingestion studies with H. pylori is somewhat limited. The available evidence does suggest a period of transient achlorhydria lasting for up to perhaps 2-3 weeks after infection, and this may even be preceded by a short period of marked increase in basal acid secretion (Hunt, 1989). Other bacterial infections have also been observed to be associated with reductions in acid secretion. Histamine-fast achlorhydria has been described in patients suffering from typhoid, paratyphoid, pulmonary tuberculosis, bronchopneumonia and lung abscess (Berglund and Chang, 1929). It is interesting to note that William Beaumont had previously made similar observations on the reduction in gastric secretion occurring in the gastric fistula subject, Alexis St Martin, during a febrile illness, remarking ‘. . . the secretions become greatly vitriated, greatly diminished or entirely suppressed. . .’ (Hunt, 1989). Some parasitic infections, including the fish tapeworm Diphyllobothrium latum, Trypanosoma cruzi (the causative agent in Chagas’ disease) and the hookworm Ancylostoma duodenale, may also reduce gastric acid secretion by mechanisms that are currently unknown (Hunt, 1989). ACID

SECRETION

AND SMALL

INTESTINAL

FLORA

In normal individuals the upper small intestine is either completely sterile or contains relatively small numbers of bacteria. Whilst the oropharyngeal flora has great relevance to that found in the stomach, the intragastric milieu appears to have most influence on the bacterial population of the small bowel (Drasar et al, 1969). The species represented in the small intestine

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usually reflect the oropharyngeal and intragastric flora. Coliforms or anaerobes are not usually detectable (King and Toskee, 1979). Bacterial counts do rise after food, perhaps to levels of around lo5 organisms/ml, but in normal individuals decline soon after to undetectable levels. Gastric surgery certainly does appear to increase jejunal bacterial counts, especially when gastrectomy, gastrojejunostomy or vagotomy and antrectomy have been carried out (Drasar and Shiner, 1969). Coliform contamination also appears common, especially after the former procedures. This appears much less of a problem after vagotomy and pyloroplasty (Browning et al, 1974). Similarly, in pernicious anaemia, although jejunal bacterial counts are often elevated, this is usually modest (King and Toskee, 1979). In those patients with pernicious anaemia who have positive cultures, coliforms may also be present. Little is known about the effects of acid suppressive treatment on jejunal flora (Ruddell and Losowsky, 1980). CONCLUSION Apart from a transient flora after meals or drinks, the healthy stomach and small intestine appear relatively sterile. Any bacteria that do appear are normally representative of oral flora. Gastric acid secretion appears to be a major controlling factor for bacterial growth in the upper gastrointestinal tract. In patients with reduced acid secretion, including those with pernicious anaemia, following resectional gastric surgery and those receiving the Hz-receptor antagonists and proton pump inhibitor drugs, bacterial numbers rise. The variety of organisms can also change in these situations and may include ‘faecal-type’ organisms. Increased numbers of nitratereducing organisms can also be present, together with increased luminal nitrite concentrations. Whether these changes have any clinical significance, and particularly in relation to the development of gastric cancer, has been extensively investigated and debated and yet remains controversial. Other clinical effects of acid suppression on bacterial flora relate to anecdotal reports of increased intestinal infection with pathogens, including salmonella, and an apparent increased risk of pulmonary infection in intensive care patients. The organism H. pylori is one relatively remarkable exception in that it appears to colonize gastric mucosa in large numbers of the population. H. pylori is associated with elevated gastrin levels but in the long term has apparently little direct effect on acid secretion. The strong association with gastric cancer and the effects of H. pylori colonization on gastric secretion of ascorbic acid may imply a role for the bacterium in the pathogenesis of gastric cancer. Although gastric acid kills H. pylori, acid suppressant treatment appears to have little effect on growth of this organism. However, recent evidence suggests that the combination of a proton pump inhibitor with an antibacterial agent may eradicate H. pylori from gastric mucosa. The discovery of H. pylori and its relation to acid secretion has rekindled interest in the association of bacteria within the stomach and acid secretion. Whilst gastric acid is obviously not the only factor influencing bacterial

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colonization within the stomach and upper small intestine, it is without doubt important. The debate concerning the relationship of long-term acid suppression and the subsequent development of gastric cancer appears set to continue and will presumably achieve greater importance as more potent inhibitors of acid secretion are developed. Interference with normal gastric acid secretion obviously has important effects on the physiology of the intestine and undoubtedly much remains to be discovered about the longterm effects of such changes.

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of nitrosated

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